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Published August 28, 2024 | Version v1
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IGF2BP3 promotes mRNA degradation through internal m7G modification

Creators

  • 1. University of Chicago
  • 2. Peking University

Description

Recent studies have suggested that mRNA internal m7G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m7G. Such interactions, especially IGF2BP3 with m7G, could promote the degradation of m7G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m7G modification, while IGF2BP1 prefers m6A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m7G-modified at its 3'UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m7G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity.

Data availability

The data supporting the findings of this study are available from the corresponding authors upon request. m7G-MeRIP-seq in WT HepG2 cells, knockdown control cells, and METTL1 stable knockdown HepG2 cells, and m7G-seq in HepG2 cells were downloaded and re-analyzed in this study (GSE112276). The sequencing data produced in this study have been deposited in Gene Expression Ominibus (GEO) repository under the accession number GSE241222. The mass spectrometry proteomics data generated in this study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD049390 and 10.6019/ PXD049390. The list of top proteins enriched by m7G probes based on the proteomics data are provided in Supplementary Data 1. The primers for dCas13b construction, guide RNA target sequences, and qPCR primers used in this study are summarized in Supplementary Data 2. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-024-51634-w
Other
oai:uchicago.tind.io:13310

Funding

Unknown funder
R01 HL155909
Unknown funder
RM1 HG008935

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Chemistry
Center(s) or Institute(s)
Institute for Biophysical Dynamics